An FDA review board laid down the law this week in an opinion memo regarding pharma giant Johnson and Johnson’s Rivaroxaban (Xarelto), stating that is not as effective as warfarin for preventing strokes in patients with atrial fibrillation and should not be approved for the new indication. However, there seem to be no increased risk factors, and the board just made the point that it is not necessarily better seemed to be the opinion’s intent.

The FDA requires that drugs approved for life-threatening conditions such as stroke, be shown to be at least as effective as other available drugs. But as the FDA reviewer pointed out, the agency “generally prefer[s] an intention-to-treat analysis as the basis of a superiority claim.”

Results from the company-sponsored ROCKET-AF study found that rivaroxaban (Xarelto) was at least as good as warfarin for stroke prevention in atrial fibrillation, with a similar rate of major bleeding and greater ease of use. Johnson & Johnson is seeking approval that indicates their drug works better at preventing strokes than warfarin.

However, there were more strokes and embolisms in the rivaroxaban group than in the warfarin group during the period when patients stopped taking their study drug and transitioned to warfarin or other appropriate therapy for the open-label portion of the study. Based on those “intent-to-treat” data, rivaroxaban was no longer superior to warfarin. It was, however, shown to work at least as well as warfarin.

Basically, the third party reviewer is recommending that the Agency (FDA) issue a complete response letter to the company rather than approve the new indication. Rivaroxaban is currently approved for prevention of DVT in patients undergoing joint replacement surgery.

Additionally, according to the FDA reviewer, the per-protocol analyses where rivaroxaban came out a winner is “misleading” because improper dosing of warfarin may have been to blame. The company did not show that when warfarin was used “skillfully,” rivaroxaban would work any better, the reviewer said.

In conclusion the review company summarized:

“Thus, the data do not convincingly demonstrate that rivaroxaban is as effective in preventing strokes and systemic emboli as warfarin when warfarin is used skillfully. Patients taking it (rivaroxaban) might be at greater risk of harm from stroke and/or bleeding than if they were treated with warfarin used skillfully. In the opinion of this reviewer, rivaroxaban should not be approved unless the sponsor submits convincing information that it is as safe and effective for its target indication as warfarin when it is used skillfully or that it is as safe and effective as another approved agent, such as dabigatran.”

On somewhat of a positive note, in its briefing documents the review company stressed the ease of use and management of rivaroxaban, which does not require INR monitoring, nor does it require dietary restrictions, both of which are required with warfarin therapy.

They continue:

“Additional medications such as rivaroxaban would give the physician a wider range of therapeutic options that can be tailored to the individual patient.”

The true bottom line in fact is that rivaroxaban-treated patients experienced numerically fewer critical organ bleeds, intracranial hemorrhages, hemorrhagic strokes, and fatal bleeds compared with patients treated with warfarin.

Guidance documents represent the Agency’s current thinking on a particular subject. They do not create or confer any rights for or on any person and do not operate to bind FDA or the public.

Written by Sy Kraft